Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The detection of early micrometastasis or disseminated single tumor cells poses a problem for conventional diagnosis procedures. Using a panel of monoclonal antibodies against cytokeratin and the 17-1A epithelial antigen we identified immunocytochemically tumor cells in bone marrow of patients with breast cancer (n = 155) and colorectal cancer (n = 57) at the time of surgery of the primary tumor. Monoclonal antibody CK2, recognizing the human cytokeratin component 18 in simple epithelia, appeared to be the most suitable reagent because of its negative reaction with bone marrow samples of the noncarcinoma patients (n = 75). Its specificity was further demonstrated in a double-marker staining procedure using an anti-leukocyte common antigen monoclonal antibody (T200) as counterstain. A comparative analysis showed that immunocytology was clearly superior to conventional cytology (n = 212) and histology (n = 39). In 9.5-20.5% of patients without distant metastasis, tumor cells could be detected in bone marrow. We found a significant correlation between tumor cells in bone marrow and conventional risk factors, such as distant metastasis or lymph node involvement. In a first approach toward immunotherapy we demonstrated in 3 patients that infused monoclonal antibody 17-1A can label single tumor cells in bone marrow in vivo. We then used this approach to follow up 7 patients undergoing 17-1A therapy in an adjuvant clinical trial.
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PMID:Micrometastatic cancer cells in bone marrow: in vitro detection with anti-cytokeratin and in vivo labeling with anti-17-1A monoclonal antibodies. 244 26

Histotypic differentiation and prognosis of carcinomas are intimately linked phemonena, i.e. poorly differentiated tumors show increased invasiveness and have a worse prognosis compared to well-differentiated tumors. In poorly differentiated carcinomas, loss of epithelial cell contacts is frequently observed; this allows the cells to break away from the primary tumor and invade surrounding tissue. The molecular basis for the disturbance of epithelial junction formation in tumors has been the subject of recent research. It has become clear that the epithelial cell adhesion molecule E-cadherin and its associated proteins, the catenins, are of central importance for the establishment of the epithelial phenotype and the prevention of invasiveness, and that aberrations in these components contribute to metastasis. The molecular mechanisms controlling the E-cadherin-based adhesion system in normal epithelial cells and in invasive carcinomas are the topic of this review.
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PMID:Cell contacts, differentiation, and invasiveness of epithelial cells. 765 33

E-cadherin is a calcium-dependent, epithelial cell adhesion molecule whose reduced expression has been associated with tumor dedifferentiation and increased lymph node metastasis in clinical studies involving several carcinomas. In this study, 111 patients who had previously undergone complete resection and systematic mediastinal lymph node dissection for non-small cell lung cancer (NSCLC) were studied retrospectively. In the primary tumor, as well as in the lymph node metastases, E-cadherin expression was detected by immunohistochemistry using a monoclonal antibody (HECD-1; Takara, Otsu, Japan). There was a significant inverse correlation between E-cadherin expression and lymph node stage (Pearson correlation coefficient -0.52, p = 0.0001) as well as tumor differentiation (Pearson correlation coefficient -0.27, p = 0.005). Moreover, Kaplan and Meier survival estimates showed a significant correlation between E-cadherin expression and patient survival in log rank testing (p = 0.006). In the patient group with the highest proportion of E-cadherin positive tumor cells, 60% of the patients were still estimated to be alive at 36 mo, versus 32% of the patients in the group classified as showing negative E-cadherin expression. Our findings provide clinical evidence that reduced E-cadherin expression is associated with tumor dedifferentiation, increased lymphogenous metastasis and poor survival. It seems therefore that E-cadherin expression might be an important prognostic factor in NSCLC.
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PMID:Reduced E-cadherin expression is associated with increased lymph node metastasis and unfavorable prognosis in non-small cell lung cancer. 956 56

Immunotherapy trials using monoclonal antibodies 323/A3 and 17-1A that recognize Ep-CAM, including trials focused on cancer of the lung, currently are underway. Nevertheless, there have been few comprehensive evaluations of the expression of Ep-CAM in specific types of neoplastic processes, including cancer of the lung. The current study of 60 human subjects with squamous cell cancer (SCC) of the lung, selected at random, was undertaken (1) to examine the expression of Ep-CAM in SCC and associated uninvolved bronchial mucosa, bronchial epithelial hyperplasia, and dysplasia, and (2) to correlate the results with established prognostic indicators and survival of patients. In both the uninvolved bronchial mucosa and epithelial hyperplasia, the expression of Ep-CAM in luminal cells was significantly higher compared with its expression in the matched basal cells (P = .003, P < .0001, respectively). When Ep-CAM scores of basal and luminal cells present in uninvolved bronchial mucosa and epithelial hyperplasia were combined, we observed a statistically significant stepwise increase in Ep-CAM expression from uninvolved bronchial mucosa to epithelial hyperplasia to SCC, suggesting its involvement in malignant transformation of SCC. The expression of Ep-CAM was significantly higher in poorly to moderately differentiated SCC compared with well-differentiated SCC (P = .04). An increase in the expression of Ep-CAM with increasing size or local extent of the primary tumor approached statistical significance (P = .09). The expression of Ep-CAM increased significantly with increasing involvement of regional lymph nodes (P = .02). Similarly, the expression of Ep-CAM increased with the increasing TNM stages (P = .04). Kaplan-Meier Survival analysis using the same categorizations showed that increasing tumor size, nodal status, and stage were significantly associated with poor patient survival (P = .04, .01, .01, respectively). There was, however, no statistically significant association between patient survival and staining intensity of carcinomas for Ep-CAM. We conclude that expression of Ep-CAM increased during the progression of SCC of the lung and, therefore, may play a role in the carcinogenesis of this disease.
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PMID:The expression of Ep-CAM (17-1A) in squamous cell cancers of the lung. 1082 96

Although only less than 10% of women with primary breast cancer have clinicopathologic signs of overt metastases, metastatic relapse occurs in about half of the cases with apparently localized tumors within five years after surgery. In 23% of the patients, bone marrow metastases are detectable at first relapse and this rate even increases in patients with metastatic breast cancer. However, hematogeneous or lymphatic spread of occult tumor cells can arise before diagnosis at an early stage of primary tumor growth and is regularly underestimated by currently available clinical and pathologic staging procedures. We studied cytokeratin-positive (CK+) cells in the bone marrow (BM) and tumor markers in the blood of 128 patients with primary breast cancer in order to obtain an early diagnosis of residual disease. In a second study, we monitored cytokeratin (CK)/17-1A positive cells in the BM and peripheral blood stem cells (PBSC) to evaluate whether dose intensive or high-dose (HD)-chemotherapy can eliminate micrometastases in high-risk breast cancer patients. The overall CK+ rate was 34% (44/128 patients), 29% (15/51) for patients with T1 tumors, 33% (28/84) for N0 patients and 31% (26/82) for patients with G1-2 breast carcinoma. Interestingly, 67% of CK+ patients were only positive in one of the two BM aspirates studied. At least one tumor marker including carcinoembryonic antigen, carbohydrate antigen 15-3 and tissue polypeptide antigen, was increased in 58/128 (45%) patients [21/58 (36%) were CK+ in the BM]. Surprisingly, levels for the extracellular domain of Her-2/neu in serum samples were within the normal range in every patient studied. After a 2-year follow-up, 7/128 patients relapsed (3/7 CK+/TM-; 2/7 CK-/TM+; 2/7 CK-/TM-). We concluded that studying two BM aspirates for CK+ cells by immunocytochemistry in combination with tumor marker determination is useful for identifying patients with a higher risk for relapse. A tumor cell enrichment technique, applied in 70 patients prior to immunocytochemistry using dynabeads directly coupled to an antibody (BerEp4) targeting the 17-1A antigen, did not enhance the detection rate of disseminated tumor cells in this patient group. We monitored CK+/17-1A+ cells in the BM and PBSC and studied Her-2/neu serum levels of patients with locally advanced (n=13, group 1) and metastatic breast cancer (n=30, group 2). CK+ cells were found in the BM of 3/13 (23%) group 1 patients before but not after chemotherapy resulting in an overall survival (OS) of 92% after a median follow-up of 33 months. Contamination of PBSC in 2/9 (22%) patients was not associated with decreased survival. In group 2 patients, the CK+ rate was 60% (18/30 patients) before and 40% (4/10 patients) after therapy with an OS rate of 43% after 29 months. PBSC samples were positive in 7/24 (29%) patients. CK+ BM and PBSC led to a rapid progress and short OS whereas tumor cell free BM and PBSC resulted in a mean OS of 30 months. The antigen 17-1A was detected on most CK+ cells in both patient groups before therapy, on all CK+ PBSC and on CK+ cells in group 2 patients after therapy. Increased Her-2/neu levels were found in group 2 patients before chemotherapy. In conclusion, micrometastatic cells are present in blood and PBSC grafts of high-risk breast cancer patients and can survive even HD-chemotherapy. Immunotherapeutic target antigens on the cell surface of these cells support the idea that a combined chemoimmunotherapy might be successful in eliminating minimal residual disease.
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PMID:A summary of two clinical studies on tumor cell dissemination in primary and metastatic breast cancer: methods, prognostic significance and implication for alternative treatment protocols (Review). 1195

In breast cancer, about 35% of patients without any clinical signs of overt distant metastases already have disseminated tumor cells in bone marrow aspirates at the time of primary therapy. A significant prognostic impact of these disseminated tumor cells has been shown by many international studies: patients with tumor cells in their bone marrow have a significantly worse prognosis than those without them. Even in malignancies where the skeletal system is not a preferred location for distant metastasis, such as ovarian cancer, early presence of minimal residual disease (MRD) is correlated with poor patient outcome. Thus, besides analysis of the primary tumor, detection of MRD can be used for assessment of patient prognosis and for prediction or monitoring of response to systemic therapy. Disseminated tumor cells are also the targets for novel tumor biological therapy approaches such as specific antibody-based therapies against target cell-surface antigens such as HER2, Ep-CAM (17-1A), and uPA-R. In breast cancer, a first antibody-based tumor therapy against HER2 (Herceptin) has already been approved for clinical use in recurrent disease. However, patient selection for such tumor biological therapies becomes rather difficult due to phenotype changes, which may manifest themselves as differences between primary lesion and disseminated tumor cells. Therefore, not only identification of disseminated tumor cells but even more so their characterization at the protein and gene levels have become increasingly important. In conclusion, characterization of tumor biological properties of disseminated tumor cells allows identification of patients with breast cancer or gynecological malignancies at risk for relapse who are likely to benefit from systemic treatment and/or novel tumor biological therapy approaches.
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PMID:Minimal residual disease in breast cancer and gynecological malignancies: phenotype and clinical relevance. 1279 Mar 24

Occult disseminated tumor cells are the major cause of relapse in patients with primary operable breast cancer but detection and characterization of these few cells is difficult. Applying immunohistochemistry, an immunomagnetic enrichment technique (IET) and immunocytochemistry (IC), we studied 58 breast cancer patients without overt metastases for the frequency of cytokeratin-positive (CK+) bone marrow (BM) cells coexpressing the epithelial adhesion molecule 17-1A (EpCAM) and c-erbB-2 and analyzed the primary tumor for these antigens as a strategy for additional immunotherapy. The primary tumors were analyzed for the target antigens by a pathologist. Dissemination of CK+ cells was studied in 4-6 x 10(6) BM cells by IC alone. For characterization of CK+ cells, 10-15 x 10(6) BM cells were incubated with microbeads coupled to antibodies detecting the target antigens, labelled cells were separated on selection columns and the positively (BM cells carrying the target antigen) and negatively (BM cells without target antigen) selected fractions were stained for CK+ cells. The effectiveness of these methods was confirmed in cell culture models. 17-1A was detected in all primary tumors and c-erbB-2 overexpression (2+, 3+) was found in 25/58 tissue samples. In total, analyzing 15-20 x 10(6) BM cells in each patient, the detection rate for CK+ cells in the BM was 69% (40/58 patients). Interestingly, analysis of the positive and negative enrichment fractions showed that the 17-1A antigen was coexpressed on CK+ cells in only 6 patients and c-erbB-2/CK+ cells were found in only one patient. Although 17-1A and c-erbB-2 were frequently detected in the primary tumor, these antigens were rarely expressed on CK+ BM cells. Whether the applied IET is not able to detect low amounts of these target antigens has to be clarified. Nevertheless, applying cell-cycle independent protocols in clinical trials requires careful elucidation of those patients who might benefit from these therapies.
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PMID:Rare expression of target antigens for immunotherapy on disseminated tumor cells in breast cancer patients without overt metastases. 1461 76

Disseminated tumor cells (DTC) in bone marrow are independently related to poor outcome in patients with breast cancer. Phenotypic characterization of DTC may be useful to improve evaluation of the metastasizing potential of DTC and also to more accurately target aggressive tumor cells. DTC were screened in bone marrow aspirates from breast cancer patients by immunocytochemistry with an anticytokeratin (anti-CK) antibody (A45B/B3). Because the cell permeabilization and fixation required for intracellular CK staining is deleterious for mRNA, we used microaspiration to isolate single tumor cells stained with a monoclonal antibody directed against a membrane epitope, epithelial cell adhesion molecule (EpCAM), in CK-positive cases. Urokinase-type plasminogen activator receptor (uPAR) was quantified by real-time quantitative RT-PCR. The SKBR3 human breast cancer cell line was used to calibrate RT-PCR. A linear relationship was observed between the cycle threshold (Ct) of uPAR and 18S gene expression and SKBR3 cells spiked (1, 3, 7, 10 and 20) in control patient bone marrow. EpCAM-positive cells were aspirated in 21 out of 25 bone marrow specimens from breast cancer patients with CK-positive cells and uPAR mRNA expression was determined in 16 cases. A high level of uPAR mRNA in DTC was detected in 8 out of 16 patients (50%) and was associated with a more aggressive primary tumor phenotype (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative or HER2-positive) (p = 0.01). We demonstrated that real-time quantitative RT-PCR was reliably adapted to phenotype analysis of isolated micrometastatic cells. A larger study would be useful to confirm the importance of uPAR to define higher risk subgroups of breast cancer patients with micrometastatic disease.
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PMID:Real-time quantitative PCR determination of urokinase-type plasminogen activator receptor (uPAR) expression of isolated micrometastatic cells from bone marrow of breast cancer patients. 1554 15

Tetraspanins are integral membrane proteins involved in a variety of physiological and pathological processes. In cancer, clinical and experimental studies have reported a link between tetraspanin expression levels and metastasis. Tetraspanins play a role as organizers of multimolecular complexes in the plasma membrane. Indeed each tetraspanin associates specifically with one or a few other membrane proteins forming primary complexes. Thus, tetraspanin-tetraspanin associations lead to a molecular network of interactions, the "tetraspanin web." We performed a proteomic characterization of the tetraspanin web using a model of human colon cancer consisting of three cell lines derived from the primary tumor and two metastases (hepatic and peritoneal) from the same patient. The tetraspanin complexes were isolated after immunoaffinity purification using monoclonal antibodies directed against the tetraspanin CD9, and the associated proteins were separated by SDS-PAGE and identified by mass spectrometry using LC-MS/MS. This allowed the identification of 32 proteins including adhesion molecules (integrins, proteins with Ig domains, CD44, and epithelial cell adhesion molecule) (EpCAM), membrane proteases (ADAM10, TADG-15, and CD26/dipeptidyl peptidase IV), and signaling proteins (heterotrimeric G proteins). Importantly some components were differentially detected in the tetraspanin web of the three cell lines: the laminin receptor Lutheran/B-cell adhesion molecule (Lu/B-CAM) was expressed only on the primary tumor cells, whereas CD26/dipeptidyl peptidase IV and tetraspanin Co-029 were observed only on metastatic cells. Concerning Co-029, immunohistofluorescence showed a high expression of Co-029 on epithelial cells in normal colon and a lower expression in tumors, whereas heterogeneity in terms of expression level was observed on metastasis. Finally we demonstrated that epithelial cell adhesion molecule and CD9 form a new primary complex in the tetraspanin web.
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PMID:Profiling of the tetraspanin web of human colon cancer cells. 1646 80

The presence of tumor-initiating cells (CD44(+)/CD24(-)) in solid tumors has been reported as a possible cause of cancer metastasis and treatment failure. Nevertheless, little is know about the presence of CD44(+)/CD24(-) cells within the primary tumor and metastasis. The proportion of CD44(+)/CD24(-) cells was analyzed in 40 samples and in 10 lymph node metastases using flow cytometry phenotyping. Anti-human CD326 (EpCam; FITC), anti-human CD227 (MUC-1; FITC), anti-human CD44 (APC), and anti-human CD24 (PE), anti-ABCG2 (PE), and anti-CXCR4 (PeCy7) were used for phenotype analysis. The mean patient age was 60.5 years (range, 33-87 years); mean primary tumor size (pT) was 1.8 cm (0.5-3.5 cm). The Wilcoxon or Kruskal-Wallis test was used for univariate analyses. Logistic regression was used for multivariate analysis. The median percentage of CD44(+)/CD24(-) cells within primary invasive ductal carcinomas (IDC) was 2.7% (range, 0.2-71.2). In lymph node metastases, we observed a mean of 6.1% (range, 0.07-53.7). The percentage of CD44(+)/CD24(-) cells in IDCs was not associated with age, pT, tumor grade and HER2. We observed a significantly enrichment of CD44(+)/CD24(-) and ABCG2(+) cells in ESA(+) cell population in patients with positive lymph nodes (P = 0.02 and P = 0.04, respectively). Our data suggest that metastatic dissemination is associated with an increase in tumor-initiating cells in stage I and II breast cancer.
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PMID:CD44+/CD24- cells and lymph node metastasis in stage I and II invasive ductal carcinoma of the breast. 2171 50


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